Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we showed that apoptosis is involved in N -methyl- D -aspartate (NMDA) induced excitotoxicity in adult rat retinas. Since rabbits have a higher endogenous level of glutamate in the retina and very different retinal structures, it is not clear if apoptosis is similarly involved in adult rabbit retinas after intravitreal injection of NMDA. In this study, we used ultrastructural features, TdT-mediated biotin-dUTP nick end labeling (TUNEL) and two caspase inhibitors to examine whether apoptosis is involved in NMDA-induced excitotoxicity in adult rabbit retinas. At 18 hr after an intravitreal injection of 400 nmoles NMDA, typical apoptotic features in degenerative cells in the retinal ganglion cell layer (RGCL) and the inner nuclear layer (INL) were noted by electron microscopy. TUNEL positive nuclei were detected in these layers as early as 4 hr showing maximal numbers at 18 hr. At 7 days, significant loss of nuclei from the RGCL was noted at the visual streak, the superior and the inferior retinas. These losses were abolished by simultaneous administration of MK-801 and ameliorated by YVAD, a caspase-1 inhibitor, but not by IETD, a caspase-8 inhibitor. These results indicated that, similar to adult rat retinas, apoptosis is involved in NMDA receptor-mediated excitotoxicity in rabbit retinas and that specific caspases may play important roles.
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PMID:N -methyl- D -aspartate (NMDA) induced apoptosis in adult rabbit retinas. 1099 63

Cell death induced by etoposide in the human lymphoma cell line U-937 GTB was characterized. Activity of caspases -3, -8 and -9 was measured by spectrophotometric detection of specific cleavage products, DNA fragmentation by TdT-mediated dUTP nick end-labelling (TUNEL), and apoptotic morphology by conventional staining and microscopy, as well as by a novel method-the microculture kinetics (MiCK) assay. Synthesis of protein and DNA during exposure was monitored by incorporation of radioactive leucine and thymidine, respectively. The effects of caspase inhibitors on total viability, as well as early and late morphological changes were studied. Etoposide rapidly induced apoptosis, dependent on caspase-3 and -8, but inhibition of these caspases did not prevent major cell death, but promoted a switch in late morphology. The novel MiCK assay added valuable information on early morphological events during cell death. Hence, this study provides support for caspase-8-mediated apoptosis in U-937 GTB when exposed to etoposide. General caspase inhibition switches cell death to one with a different morphology.
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PMID:Characteristics of etoposide-induced apoptotic cell death in the U-937 human lymphoma cell line. 1160 58

Proliferation and matrix synthesis by activated pancreatic stellate cells (PSC) participate in the development of chronic pancreatitis. Apoptosis of PSC may terminate this process but has not yet been studied in this particular cell type and was the aim of the present study. PSC were isolated from rat pancreas and characterized for expression of glial fibrillary acidic protein, alpha-smooth muscle actin, CD95, and tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) receptors. Apoptosis was determined by TdT-UTP nick end-labeling reaction, annexin V binding, and caspase-8 activation. Both CD95L and TRAIL induced apoptosis in PSC. The apoptotic response was minor in PSC cultured for 7 days but increased markedly thereafter. Sensitization of PSC with culture duration was accompanied by increased expression of CD95 and TRAIL receptor 2 and no alterations of Flip expression or protein kinase B phosphorylation but was paralleled by the appearance of a COOH-terminal cleavage product of receptor-interacting protein. PSC apoptosis was also induced by PK-11195, a ligand of the peripheral benzodiazepine receptor. PSC apoptosis may be important in terminating the wound-healing response after pancreas injury and exhibits features distinct from apoptosis induction in hepatic stellate cells.
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PMID:Apoptosis in activated rat pancreatic stellate cells. 1218 Nov 99

The expression of the apoptosis inducer Fas (CD95/APO-1) surface receptor by human foetal neurons was investigated in vitro and ex vivo. Immunofluorescence studies of brain and spinal cord cells in primary cultures and of cryosections obtained from 9- and 10-week-old human foetuses, respectively, showed that all Fas-expressing cells were motoneurons (5.3 and 4.2% of the neurons in brain or spinal cord cultures, respectively) on the basis of morphology, reactivity with the monoclonal antibody SMI-32, a mostly motoneuronal marker and acetylcholine esterase expression. Fas was undetectable on the other cell types in culture. The ability of Fas to induce apoptosis of cultured cells from both tissues was determined by using the terminal transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) method combined with the same double-staining procedure. Under basal culture conditions, about 9% of cells, all glial fibrillary acidic protein-expressing astrocytes, were apoptotic. After a 48-h incubation with Fas ligand, mean 28.5% of brain motoneurons and 29.4% of spinal motoneurons underwent apoptosis, with an inhibition by Z-IETD-FMK, a caspase-8 inhibitor. Hence, Fas appears to be functional through a caspase-8-dependent pathway in a subpopulation of human foetal motoneurons.
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PMID:Expression of a functional Fas death receptor by human foetal motoneurons. 1277 May 53

2-Oxo-3,23-isopropylidene-asiatate (AS2006A), a wound-healing asiatate derivative, exerts anti-inflammatory effect. Macrophages produce cytokines that recruit other inflammatory cells and are responsible for the diverse effects of inflammation. In the present study, we comparatively evaluated the cytotoxicity of AS2006A to Raw264.7, H4IIE and L-929 cells as part of the studies on its anti-inflammatory effect. Among the cells examined, AS2006A was selectively cytotoxic to Raw264.7 cells, a macrophage cell line. AS2006A increased the number of cells positively stained with TdT-mediated dUTP nick end labeling (TUNEL), and upregulated the expression of the genes implicated with apoptosis, which included caspase-8, c-myc, iNOS, mdm2, NF-kappaB1, I-kappaBalpha and NF-kappaB p105 genes, as assessed by the membrane DNA array technique. The expression of the genes related with cell cycle control was not changed. Thus, the primary targets of AS2006A in macrophages might include the genes implicated with apoptosis. Immunoblot analysis revealed that AS2006A caused the release of cytochrome c from the mitochondria to the cytoplasm in macrophages. Caspase-3 activity and poly(ADP-ribose) polymerase cleavage were both increased by AS2006A in macrophages, indicating that AS2006A induced apoptosis. Viability of macrophages activated by lipopolysaccharide and their NO production were also decreased by AS2006A in a concentration-dependent manner. These results demonstrated that AS2006A selectively induces apoptosis of macrophages with cytochrome c release, caspase 3 activation and poly(ADP-ribose) polymerase cleavage, and that cytotoxicity of AS2006A to macrophages may contribute to anti-inflammatory and wound-healing effects.
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PMID:2-Oxo-3,23-isopropylidene-asiatate (AS2006A), a wound-healing asiatate derivative, exerts anti-inflammatory effect by apoptosis of macrophages. 1294 39

Stat5a/b exhibits 96% homology and are required for normal immune function. The present studies examined Stat5a/b function in lymphoid cells by specific and simultaneous disruption of both proteins using novel phosphorothioate-2'-O-methoxyethyl antisense oligodeoxynucleotides (asODN). Efficient delivery was confirmed by the presence of fluorescent TAMRA-labeled ODN in >or=55 and 95% in human primary and tumor cell lines, respectively. Acute asODN administration reduced levels of Stat5a (90%) in 6 h, whereas Stat5b required nearly 48 h to attain the same inhibition, suggesting that the apparent turnover rate for Stat5a was 8-fold higher than that for Stat5b. Expression of the closely related Stat3 protein was unchanged after asODN treatment, however. Molecular ablation of Stat5a/b promoted apoptotic cell death in a significant population of primary PHA-activated T cells (72%) and lymphoid tumor cell line (e.g., YT; 74%) within 24 h, as assessed by 1) visualization of karyolytic nuclear degeneration and other generalized cytoarchitectural alterations, 2) enzymatic detection of TdT-positive DNA degradation, and 3) automated cytometric detection of annexin V translocation. Contrary to findings from Stat5a/b-null mice, cell cycle progression did not appear to be significantly affected. Interestingly, IL-2-insensitive and unprimed T cells and Jurkat cells remained mostly unaffected. Finally, evidence is provided that the cytotoxicity associated with Stat5a/b ablation may derive from activation of caspase-8, an initiator protease that contributes to apoptotic cell commitment. We propose that in lymphoid cells competent to activate Stat5a and Stat5b, both proteins preferentially mediate an antiapoptotic survival influence.
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PMID:Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells. 1453 Mar 8

Tumour necrosis factor-alpha (TNF-alpha)-induced intestinal epithelial cell apoptosis may contribute to mucosal injury in inflammatory bowel disease. Inhibition of TNF-alpha-induced apoptosis, using specific caspase inhibitors could, therefore, be of benefit in the treatment of disease. In vitro, CaCo-2 colonic epithelial cells are refractory to apoptosis induced by TNF-alpha alone; however, TNF-alpha can act synergistically with the short-chain fatty acid (SCFA) and colonic fermentation product, butyrate, to promote apoptosis. TNF-alpha/butyrate-induced apoptosis was characterised by nuclear condensation and fragmentation and caspase-3 activation. Inhibitors of caspase-8 (z-IETD.fmk) and caspase-10 (z-AEVD.fmk) significantly reduced TNF-alpha/butyrate-induced apoptosis, based on nuclear morphology and terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labelling (TUNEL), although caspase inhibition was associated with a significant increase in cells demonstrating atypical nuclear condensation. Inclusion of atypical cells in calculations of total cell death, still demonstrated that z-IETD.fmk and z-AEVD.fmk (in combination) significantly reduced cell death. Reduction in cell death was associated with maintenance of viable cell number. Transmembrane resistance was also used a measure of the ability of caspase inhibitors to prevent TNF-alpha/butyrate-mediated damage to epithelial monolayers. TNF-alpha/butyrate resulted in a significant fall in transmembrane resistance, which was prevented by pre-treatment with z-IETD.fmk, but not z-AEVD.fmk. In conclusion, synthetic caspase inhibitors can reduce the apoptotic response of CaCo-2 colonic epithelial cells to TNF-alpha/butyrate, improve the maintenance of viable cell numbers and block loss of transmembrane resistance. We hypothesise that caspase inhibition could be a useful therapeutic goal in the treatment of inflammatory bowel conditions, such as ulcerative colitis.
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PMID:The effect of specific caspase inhibitors on TNF-alpha and butyrate-induced apoptosis of intestinal epithelial cells. 1472 May 4

We investigated the effect of pressure levels ranging from 80 to 500 bar on the proliferative capacity and viability of Jurkat leukaemic T cells. Pressurization at 360 bar induced apoptotic cell death as shown by apoptotic morphology after Hoechst staining, DNA fragmentation in the TdT-mediated dUTP nick end labelling-assay and cleavage of several caspase substrates. Cell death could be prevented by the general caspase inhibitor zVAD-fmk. Breakdown of the mitochondrial membrane potential and the release of cytochrome c provided strong evidence for an involvement of the mitochondrial pathway, whereas a central role of the death receptor pathway was excluded because caspase-8 was not significantly activated. Pressure incubation led to calcium influx after 5 min, and we hypothesize that calcium influx could be the primary trigger for pressure-induced apoptosis.
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PMID:Hydrostatic pressure induces apoptosis in the human leukaemic T-cell line Jurkat via the mitochondrial pathway. 1537 65

GD3 ganglioside induces apoptosis in several cell types, but the molecular events through which this occurs are largely unknown. We investigated the apoptotic effects of GD3 expression using U-1242 MG glioblastoma cells, as these cells synthesize almost exclusively GM3 and GM2 but not GD3. To express GD3 under the control of the TetOn system with minimum leakage, we modified the system by constructing a single tri-cistronic retrovirus vector containing three genes separated by two internal ribosome entry sites: (a) transcriptional silencer, tTS; (b) mutant of reverse transcriptional activator, rtTA2(S)-M2 (provided by H. Bujard, Heidelberg, Germany); and (c) enhanced green fluorescent protein (EGFP), as an indicator of the tri-cistronic gene expression. Using flow cytometry, we selected glioma cells (U1242MG-GD3 clone) that express high levels of GD3 in response to doxycycline. Expression of GD3 was associated with apoptosis as verified by annexin-V binding, TdT-mediated dUTPnick end-labelling assay (TUNEL), and EGFP degradation. GD3-induced apoptosis occurred via caspase-8 activation, as GD3 caused cleavage of caspase-8 and inhibition of caspase-8 activation by zlETD-fmk minimized GD3-induced apoptosis.
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PMID:Endogenous GD3 ganglioside induces apoptosis in U-1242 MG glioma cells. 1644 17

Anaplastic thyroid carcinoma (ATC) is one of the most malignant tumors in humans, and currently there is no effective treatment. In the present study we investigated the effect of an endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), on the growth of human ATC cells. 2-ME treatment had a strong growth inhibitory effect on five human ATC cell lines (HTh7, HTh 74, HTh83, C643, and SW1736), but showed no effect on one cell line (KAT-4). Cell cycle analysis of the growth-inhibited cells showed that 2-ME induced a G2/M-arrest, followed by an increased fraction of cells in sub-G1. Analysis of internucleosomal DNA laddering as well as DNA fragmentation in a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay demonstrated a high number of cells undergoing apoptosis after 2-ME treatment. An increased activation of caspase-3 and caspase-8 by 2-ME was observed, and inhibition of caspase-3 decreased the apoptotic effect. Addition of 2-ME increased activity of p38 mitogen-activated protein kinase (MAPK) in the sensitive HTh7 as well as the refractory KAT-4 cells, however, activation of stress-activated protein kinase/c-jun aminoterminal kinase (SAPK/JNK) was seen only in the HTh7 cells. Inhibitors of p38 MAPK and SAPK/JNK significantly attenuated the 2-ME effect. Taken together, our data demonstrate an antiproliferative and apoptotic effect of 2-ME on ATC cells involving activation of MAPKs.
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PMID:2-methoxyestradiol induces apoptosis in cultured human anaplastic thyroid carcinoma cells. 1667 99


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